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Hyperglycemia Stimulates Coagulation, Whereas Hyperinsulinemia Impairs Fibrinolysis in Healthy Humans

¹ Center for Infection and Immunity Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
² Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
³ Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
⁴ Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
⁵ Department of Clinical Epidemiology and Biostatistics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands

Address correspondence and reprint requests to Michiel E. Stegenga, MD, Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, G2-130, Meibergdreef 9, 1105 AZ Amsterdam, Netherlands. E-mail: m.e.stegenga{at}amc.uva.nl

Abbreviations: CVD, cardiovascular disease; H_insuE_gluc, hyperinsulinemic-euglycemic; H_insuH_gluc, hyperinsulinemic-hyperglycemic; L_insuE_gluc, lower insulinemic-euglycemic; L_insuH_gluc, lower insulinemic-hyperglycemic; PAI-1, plasminogen activator inhibitor type 1; TATc, thrombin-antithrombin complex; tPA, tissue-type plasminogen activator

Type 2 diabetes and insulin resistance syndromes are associated with an increased risk for cardiovascular and thrombotic complications. A disturbed balance between coagulation and fibrinolysis has been implicated in the pathogenesis hereof. To determine the selective effects of hyperglycemia and hyperinsulinemia on coagulation and fibrinolysis, six healthy humans were studied on four occasions for 6 h: 1) lower insulinemic-euglycemic clamp, 2) lower insulinemic-hyperglycemic clamp, 3) hyperinsulinemic-euglycemic clamp, and 4) hyperinsulinemic-hyperglycemic clamp. In the hyperglycemic clamps, target levels of plasma glucose were 12 versus 5 mmol/l in the normoglycemic clamps. In the hyperinsulinemic clamps, target plasma insulin levels were 400 versus 100 pmol/l in the lower insulinemic clamps. Hyperglycemia exerted a procoagulant effect irrespective of insulin levels, as reflected by mean twofold rises in thrombin-antithrombin complexes and soluble tissue factor, whereas hyperinsulinemia inhibited fibrinolysis irrespective of glucose levels, as reflected by a decrease in plasminogen activator activity levels due to a mean 2.5-fold rise in plasminogen activator inhibitor type 1. The differential effects of hyperglycemia and hyperinsulinemia suggest that patients with hyperglycemia due to insulin resistance are especially susceptible to thrombotic events by a concurrent insulin-driven impairment of fibrinolysis and a glucose-driven activation of coagulation.

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